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SnapShot: Glioblastoma Multiforme 10 G C RE S E N€¦ · SnapShot: Glioblastoma Multiforme...

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10 E X C I T I N G C A N C E R R E S E A R C H E X C I T I N G C A N C E R R E S E A R C H S I N C E 2 0 0 2 S I N C E 2 0 0 2 YEARS OF YEARS OF GSC neurosphere in vitro Pseudopallisading necrosis in GBM MRI scan of a GBM PROLIFERATION INVASION METABOLISM ANGIOGENESIS Glioblastoma cell Extracellular matrix BAI1 8, 30 28 4 28 27, 43 4 29, 34 1, 25 55 54 27, 43 20 20 1, 25 10, 17, 19, 45 8, 30 5, 9, 14 THBS1 VEGF MET, EGFR, PDGFR MET MAPK TRKA PGK1 GLUT1 VEGF mTOR DNA damage mTOR RAS PI3K AKT NF1 PTEN MAPK pathway S-phase genes ARF/MDM2/p53 RB INK4A Aberrant metabolism HIF1a MYC p53 PHD D-2-HG Histone demethylases G-CIMP phenotype TET family a-KG a-KG b-oxidation IDH2 Acetyl-CoA Fatty acids Pyruvate Glucose Glycolysis Fatty acid synthesis Isocitrate Citrate Mut IDH1 IDH1 NADPH NADPH NADP + NADP + Glutamate Glutamine GLS GSH Reactive oxygen species Mutation GAB1 SHP2 GRB2/SOS NF1 RAS RAF MIRK (DYRK1B) RANBPM (RANBP9) ZEB1 E-cadherin uPA MMPs Migration, Invasion ITGB1 TRAF6 I kB Apoptosis Proliferation p53 Hypoxia PI3K pathway, Mut IDH1 HIF1a SCF PIGF ANGPT1/2 BFGF PDGF a Vb 5 NF-kB CD36, a Vb 3 a Vb 5 VEGFR2 KIT PIGFR MAPK & PI3K pathways EC division, vascular permeability, EC migration, mobilization of BM-EPCs TIE2 FGFR PDGFR Notch Endothelial cell GLIOMA STEM CELLS Normal differentiation pathway Gliomagenesis Clonal evolution model Notch Oligodendrocyte Neuron Progenitor cell Astrocyte Astrocytoma Oligodendroglioma OA mixed NSC Notch, SHH/GLI, STAT3 GSC Cell cycle arrest CTGF HGF (SF) Krebs cycle Nucleus Mitochondria (5mC-Hydroxylases) Brain whole mount with GBM Tumor mass Tumor mass Microvascular proliferation Microvascular proliferation Invading cells Invading cells Hypoxia Hypoxia CTGF CTGF Reactive astrocytes Reactive astrocytes DLL # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 35 37 39 41 43 45 47 49 51 34 36 38 40 42 44 46 48 50 52 53 54 55 Rilotumumab Aflibercept Afatimib Bevacizumab Brivanib Cediranib Cetuximab Cilengtide Lenvatinib mesylate Enzastaurin Erlotinib Gefitinib Imatinib Intedanib Lapatinib BKM120 Nelfinavir Pazopanib Perifosine Sorafenib Sunitinib Tandutinib Temsirolimus Vandetanib Cabozantinib XL765 Tipifarnib R04929097 Veliparib ATN-161 AZD8055 AZD2014 BKM120 Rindopepimut Matuzumab Foretinib Olavatumab Lonafarnib MK2206 Dacomitinib Panobinostat Sirolimus Iniparib Pegdinetanib Everolimus Ramucirumab I-125 MAB-425 ABT-806 Nimotuzumab PX-866 Ridaforolimus Vatalanib XL147 Bortezomib AZD7451 DRUG 3, 7, 11, 12, 15, 24, 25, 35, 37, 42, 44, 46, 47 6, 9, 13, 14, 18, 20, 21, 22, 41, 52 2, 5, 6, 9, 14, 18, 20, 21, 24, 25, 36, 39, 40, 52 6, 13, 18, 20, 21, 22, 25 23, 26, 31, 32, 38, 50, 51 10, 16, 26, 33, 48, 53 These pharmacological agents affect targets shown in red. SnapShot: Glioblastoma Multiforme Svetlana Kotliarova and Howard A. Fine Center for Cancer Research, National Cancer Institute, National Institutes for Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. See online version for legend and references. 710 Cancer Cell 21, May 15, 2012 ©2012 Elsevier Inc. DOI 10.1016/j.ccr.2012.04.031 Culture brain tumor stem cells (BTSCs) with NeuroCult™ NS-A (Catalog #05751): SPECIALIZED. Formulated to maintain human neural stem cells and BTSCs in long-term culture. VERSATILE. Supports isolation and proliferation of BTSCs from a variety of tumor types, using either neurosphere or monolayer culture techniques. CONSISTENT. Conforms to STEMCELL Technologies’ stringent quality control standards, including rigorous performance testing using primary cells. STEMCELL Technologies is committed to making sure your research works. As Scientists Helping Scientists, we support our customers by creating novel products with consistent un- failing quality and by providing unparalleled technical support. Identify and isolate viable BTSCs: NeuroFluor™ CDr3 (Catalog #01800) for detection and isolation of BTSCs based on FABP7 expression (Yun et al., PNAS 2012). ALDEFLUOR™ (Catalog #01700) for detection and isolation of BTSCs based on aldehyde dehydrogenase (ALDH) enzyme activity.
Transcript
Page 1: SnapShot: Glioblastoma Multiforme 10 G C RE S E N€¦ · SnapShot: Glioblastoma Multiforme Svetlana Kotlia rova and Howa d A. Fine Center for Cancer Research, National Cancer Institute,

10EX

CIT

ING

CA N C E R RE

SE

AR

CH

EX

CIT

ING

CA N C E R RE

SE

AR

CH

SIN C E 2 0 02

SIN C E 2 0 02

YEARS OFYEARS OF

GSC neurosphere in vitroPseudopallisadingnecrosis in GBM

MRI scan of a GBM

PROLIFERATION

INVASION

METABOLISM

ANGIOGENESIS

Glioblastoma cell

Extracellular matrix BAI1

8, 3028

4

28

27, 43

4

29, 34

1, 25 55

5427, 43

20

20

1, 25

10, 17, 19, 45

8, 30 5, 9, 14

THBS1 VEGF

MET, EGFR, PDGFR

MET

MAPK

TRKA

PGK1GLUT1VEGF

mTOR

DNAdamage

mTOR

RAS PI3K

AKT

NF1

PTEN

MAPKpathway

S-phasegenes

ARF/MDM2/p53

RBINK4A

Aberrantmetabolism

HIF1a

MYC p53

PHD

D-2-HG

Histone demethylases

G-CIMP phenotype

TET family

a-KG

a-KG

b-oxidation

IDH2Acetyl-CoA

Fatty acids

Pyruvate

GlucoseGlycolysis

Fatty acid synthesisIsocitrate

CitrateMut IDH1IDH1

NADPH

NADPH

NADP+

NADP+Glutamate

GlutamineGLS

GSH

Reactive oxygen species

Mutation

GAB1

SHP2

GRB2/SOS

NF1RAS

RAF

MIRK (DYRK1B)

RANBPM(RANBP9)

ZEB1

E-cadherinuPAMMPs Migration, Invasion

ITGB1

TRAF6

IkB

Apoptosis

Proliferation

p53 Hypoxia PI3K pathway, Mut IDH1

HIF1a

SCF PIGF ANGPT1/2 BFGF PDGF

aVb5

NF-kB

CD36,aVb3aVb5

VEGFR2 KIT PIGFR

MAPK & PI3K pathways

EC division, vascular permeability, EC migration, mobilization of BM-EPCs

TIE2 FGFR PDGFRNotchEndothelial cell

GLIOMA STEM CELLSNormal differentiation pathway Gliomagenesis Clonal evolution model

Notch

OligodendrocyteNeuron Progenitor

cell

Astrocyte Astrocytoma

Oligodendroglioma

OA mixed

NSC

Notch, SHH/GLI, STAT3

GSC

Cell cyclearrest

CTGFHGF (SF)

Krebscycle

Nucleus

Mitochondria

(5mC-Hydroxylases)

Brain whole mount with GBMTumor massTumor mass

MicrovascularproliferationMicrovascularproliferation

Invadingcells

InvadingcellsHypoxiaHypoxia

CTGFCTGF

ReactiveastrocytesReactive

astrocytes

DLL

#123456789101112131415161718192021222324252627282930313233

35

37

39

41

43

45

47

49

51

34

36

38

40

42

44

46

48

50

52535455

RilotumumabAfliberceptAfatimibBevacizumabBrivanibCediranibCetuximabCilengtideLenvatinib mesylateEnzastaurinErlotinibGefitinibImatinibIntedanibLapatinibBKM120NelfinavirPazopanibPerifosineSorafenibSunitinibTandutinibTemsirolimusVandetanibCabozantinibXL765TipifarnibR04929097VeliparibATN-161AZD8055AZD2014BKM120

Rindopepimut

Matuzumab

Foretinib

Olavatumab

Lonafarnib

MK2206

Dacomitinib

Panobinostat

Sirolimus

Iniparib

Pegdinetanib

Everolimus

Ramucirumab

I-125 MAB-425

ABT-806

Nimotuzumab

PX-866

Ridaforolimus

VatalanibXL147BortezomibAZD7451

DRUG

3, 7, 11, 12, 15, 24, 25, 35, 37, 42, 44, 46, 47

6, 9, 13, 14, 18, 20, 21, 22, 41, 52

2, 5, 6, 9, 14, 18, 20, 21, 24, 25, 36, 39, 40, 52

6, 13, 18, 20, 21, 22, 25

23, 26, 31, 32, 38, 50, 51

10, 16, 26, 33, 48, 53

These pharmacological agents affect targets shown in red.

SnapShot: Glioblastoma MultiformeSvetlana Kotliarova and Howard A. FineCenter for Cancer Research, National Cancer Institute, National Institutes for Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

See o

nline version fo

r legend

and references.

710 C

ancer Cell 21, M

ay 15, 2012 ©2012 E

lsevier Inc. D

OI 10.1016/j.ccr.2012.04.031

Culture brain tumor stem cells (BTSCs) with NeuroCult™ NS-A (Catalog #05751):

SPECIALIZED. Formulated to maintain human neural stem cells and BTSCs in long-term culture.

VERSATILE. Supports isolation and proliferation of BTSCs from a variety of tumor types, using either neurosphere or monolayer culture techniques.

CONSISTENT. Conforms to STEMCELL Technologies’ stringent quality control standards, including rigorous performance testing using primary cells.

STEMCELL Technologies is committed to making sure your research works. As Scientists Helping Scientists, we support our customers by creating novel products with consistent un-failing quality and by providing unparalleled technical support.

Identify and isolate viable BTSCs:

NeuroFluor™ CDr3 (Catalog #01800) for detection and isolation of BTSCs based on FABP7 expression (Yun et al., PNAS 2012).

ALDEFLUOR™ (Catalog #01700) for detection and isolation of BTSCs based on aldehyde dehydrogenase (ALDH) enzyme activity.

C

M

Y

CM

MY

CY

CMY

K

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